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Weight loss in Alzheimer disease^1,2

¹ From the Departments of Gerontology and Internal Medicine and Exploration of Respiratory Function and Sports Medicine, Purpan University Hospital, Toulouse, France, and INSERM U 518, Toulouse, France.

² Reprints not available. Address correspondence to B Vellas, University of Toulouse, Toulouse, France. E-mail: 101333.1462{at}CompuServe.com.

	ABSTRACT

TOP ABSTRACT INTRODUCTION WEIGHT LOSS IN ALZHEIMER... A LONGITUDINAL STUDY OF... REFERENCES

 
Background: Epidemiologic studies have shown that weight loss is commonly associated with Alzheimer disease (AD) and is a manifestation of the disease itself. The etiology of weight loss in AD appears multifactorial. Hypotheses to explain the weight loss have been suggested (eg, atrophy of the mesial temporal cortex, biological disturbances, and higher energy expenditure); however, none have been proven.

Objective: In the first part of this article, we describe weight loss in AD (epidemiologic data and hypotheses to explain weight loss and anorexia in AD). In the second part we report the results of a longitudinal study of the changes in nutritional variables in a cohort of patients with a probable diagnosis of AD.

Design: We followed subjects with AD (based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association) who were recruited from the Alzheimer's Disease Center in Toulouse. All subject underwent a nutritional, neuropsychologic, and functional evaluation. The Zarit scales were used to assess caregiver burden and caregiver reactions to the patients' behavioral and autonomic disorders.

Results: We showed that only results of the Burden Interview and the Memory and Behavior Problems Checklist, which explored caregiver burden, predicted weight loss in AD. It is possible that caregivers who consider themselves overburdened by the disease process are not willing to invest adequate resources to allow AD patients to properly nourish themselves.

Conclusion: Nutritional education programs for the caregivers of AD patients seem to be the best way to prevent weight loss and improve the nutritional status of these patients.

Key Words: Alzheimer disease • weight loss • caregiver burden • elderly • nutrition education • aging

	INTRODUCTION

TOP ABSTRACT INTRODUCTION WEIGHT LOSS IN ALZHEIMER... A LONGITUDINAL STUDY OF... REFERENCES

 
Alzheimer disease (AD) is a growing health issue and is one of the leading causes of death among elderly people. Three million people are currently affected in Europe. This disease is associated with cognitive and behavioral disorders and, frequently, with nutritional disorders such as weight loss and eating disorders. It seems important to have a better understanding of the pathogenesis of this AD-associated weight loss because it leads to reduced muscle mass, a loss of autonomy, and an increased risk of falls, decubitus ulcers, and systemic infection, which increase the burden of the disease and worsen the patient's and caregiver's quality of life.

	WEIGHT LOSS IN ALZHEIMER DISEASE

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Epidemiology
Since the beginning of the 1980s, many studies have been carried out to compare the annual weight variation in AD patients and healthy control subjects (1–12). These studies reported that weight loss frequently occurs in the first stages of the disease (3–12), although patients usually have adequate energy intakes (5). Weight loss is actually listed as a symptom consistent with the diagnosis of AD in the most commonly used criteria for diagnosis, those of the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association Work Group (13). Using data collected by the Consortium to Establish a Registry for Alzheimer's Disease, White et al (14, 15) examined the natural history of weight change and the frequency and severity of weight loss. They recruited 362 AD patients and 317 control subjects and determined the percentage of patients who lost or gained 5% of their body weight during participation in the study. The entry criteria excluded persons with advanced dementia. White et al found that almost twice as many AD patients as control subjects lost 5% of their initial body weight. The same finding was observed for a loss of 10% of initial body weight. Surprisingly, AD patients were also more likely to gain 5% of their initial body weight than were control subjects. In a recent study, White et al (16) determined the association of weight change in AD with the severity of the disease and mortality. They showed that the risk of weight loss tends to increase with the severity and progression of AD. According to these authors, weight loss is a predictor of mortality in subjects with AD, whereas weight gain appears to have a protective effect.

Individuals with dementia frequently develop serious feeding difficulties as their dementia progresses; accordingly, their weight probably decreases more over time than does that of nondemented individuals, and their survival might be compromised. To test this hypothesis, Wang et al (17) compared the weight variations over 48 mo of 2 institutionalized cohorts of subjects with dementia (n = 31 subjects with severe dementia and 48 with less-severe dementia) with those of a third cohort of institutionalized nondemented subjects (n = 26). Most of the AD patients had been diagnosed several years before the study began ( ± SD: 9.2 ± 5.4 y). The authors showed that men had a significantly higher mean body weight than did women. The longitudinal weight trends of the men and women were significantly different by two-factor repeated measures analysis of variance. The nondemented subjects had a significantly higher mean weight than did the demented patients at admission and throughout the longitudinal study period. All 3 cohorts maintained stable body weights throughout their institutional stay. The mean weights of the patients with severe dementia were similar to those with less-severe dementia. The authors concluded that dementia was not necessarily associated with continuous weight loss during institutionalization, despite the frequent occurrence of eating disorders and episodes of weight loss.

Wang et al (17) reported that of the 105 subjects they studied, 3 women developed dementia after they were institutionalized. The mean (±SD) weight of these 3 women at the time of entry to the study was 58.5 ± 18 kg compared with 64 ± 21 kg for the 18 women who did not develop dementia during the 4 y of the study. These results suggest, as described previously (18), that weight loss may precede dementia. Indeed, Barrett-Connor et al (18) studied weight changes in 299 free-living elderly subjects who were followed for 20 y before they were determined to be cognitively intact or to have mild-to-moderate dementia. For all of the men and women who received a diagnosis of AD (n = 60), there was a significant decrease in weight (5 kg) since the first evaluation.

Some hypotheses to explain weight loss
Weight loss in AD occurs frequently in the first stages of the disease, although patients usually have adequate energy intakes. Many hypotheses have been proposed to explain the weight loss.

Atrophy of the mesial temporal cortex
The mesial temporal cortex (MTC), which is involved in feeding behavior and memory, is affected in the primary stages of AD and continues to be a site of major AD pathology as the disease worsens. Grundman et al (19) showed in AD that a low body mass index correlates best and specifically with atrophy of the MTC. They suggested that there is a connection between limbic system damage and low body weight in AD. Atrophy of the MTC might contribute to weight loss through additional mechanisms other than cognitive impairments (eg, lack of food preparation, diminished skills, reduced appetite, and increased physical activity). Moreover, some disturbances associated with weight loss, such as increased cortisol (20) and tumor necrosis factor (21) concentrations or decreased estrogen concentrations (22), worsen atrophy of the MTC and, consequently, dementia itself.

Higher energy requirements
It has been suggested that AD patients have higher energy requirements than do healthy individuals, which may contribute to their unexplained weight loss (23–25). Donaldson et al (26) examined whether the resting metabolic rate, the largest component of daily energy expenditure, was higher in 25 AD patients [Mini-Mental State Examination (MMSE) score (27): 17 ± 8 (possible score of 0–30, with 30 being the best score.] than in 73 healthy, older, control subjects. Donaldson et al showed that the resting metabolic rate was not significantly different between AD patients and control subjects when measured on an absolute basis or when normalized for body composition and age. In AD patients, resting energy expenditure was adapted to body composition.

Poehlman et al (28) tested the hypothesis that daily energy expenditure would be higher in 30 AD patients with mild-to-moderate AD (MMSE score: 16 ± 8) than in 103 healthy subjects. Fat-free mass tended to be lower in AD patients than in control subjects, whereas no significant differences were noted in fat mass. Daily energy expenditure was 14% lower in AD patients than in healthy elderly subjects. This difference was explained by a lower resting metabolic rate and a lower physical activity expenditure in the AD patients. No significant difference in energy expenditure was found between the AD patients and the control subjects after adjustment for body composition. Thus, there was no evidence of an increase in daily energy expenditure linked to AD to explain the weight loss. In AD patients, energy expenditure is appropriate for their body size.

Biological disturbances
Hyperinsulinemia and insulin resistance have been reported in subjects with AD (29). However, these metabolic disturbances may be due to weight gain or physical inactivity rather than to AD per se. Furthermore, neuropeptide Y (NPY) may directly affect energy balance because of its potent effects on food intake, energy expenditure, and body weight (30). A decline in orexigenic factor concentrations, such as NPY and norepinephrine, has been reported in AD patients and may be involved in anorexia, which frequently occurs at the end of the disease (31).

Anorexia in Alzheimer disease
AD is generally associated with a progressive change in nutritional behavior. Anorexia may occur in the late stage of the disease and contribute to the associated weight loss. It may be due to physical changes [eg, decreased taste and smell functions (32), decreased appetite related to a decline in endogenous opioids, and increased satiety related to an increase in sensitivity to cholecystokinin], neuropsychiatric disorders associated with the disease (eg, memory loss, disorientation, mood disorders, indifference, and impaired judgment), a change in autonomy and dietary habits, or changes in neurotransmitter concentrations (eg, NPY and norepinephrine).

Dronabinol, one of the main components of marijuana, is associated with increased food intake. It also improves appetite and the sense of well-being and causes weight gain. Volicer et al (33) studied the effect of dronabinol in 12 hospitalized AD patients (MMSE score: 4.0 ± 7.4) who refused to eat. The study used a double-bind, placebo-controlled, crossover design with each study period lasting 6 wk. During the study period, nutritional status was monitored by weekly measurements of body weight and triceps skinfold thickness and by biological markers (eg, albumin and lymphocytes). Energy intake was also calculated. Disturbed behavior was measured by the Cohen-Mansfield Agitation Inventory (34; possible score: 0–91, with 0 being the best score). Body weight of study subjects increased more during dronabinol treatment than during the placebo periods. Energy intake did not change significantly during the study period and was similar in the placebo and dronabinol periods. Dronabinol treatment decreased the severity of disturbed behavior and this effect persisted during the placebo period in patients who received dronabinol first. It is possible, according to the authors, that the weight gain was partly caused by decreased agitation in the patients, which could have decreased their energy requirements. These results indicate that dronabinol is a promising novel therapeutic agent to treat anorexia but also to improve disturbed behavior observed in AD patients.

In summary, several epidemiologic studies have indicated an association between AD and weight loss. This weight loss could occur throughout the disease process, but it could be more common as the illness becomes more severe and anorexia develops. According to some authors (18), weight loss could be a manifestation of the disease itself. The etiology of weight loss in AD appears multifactorial and some hypotheses have been proposed to explain it (eg, atrophy of the MTC, biological disturbances, and high energy expenditure); however, none of these hypotheses has been proven.

	A LONGITUDINAL STUDY OF NUTRITIONAL STATUS IN ALZHEIMER DISEASE

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No work to date has prospectively studied the evolution of nutritional variables (weight, anthropometric and biological markers, and energy intakes) in AD patients; therefore, this longitudinal study was conducted, which followed the nutritional status of a cohort of patients diagnosed with probable AD.

Subjects and methods
Subjects
Subjects were recruited from the Alzheimer's Disease Center in Toulouse. All patients met the National Institute of Neurological and Communicative Disorders/Alzheimer's Disease and Related Disorders Association criteria for probable AD (13). Assessment batteries included a detailed case history and physical examination; cerebral computed tomography to exclude strokes, tumors, etc; blood chemistry screening to rule out thyroid dysfunction, vitamin B-12 deficiency, and other metabolic and hematologic abnormalities; as well as neuropsychologic tests to establish the above cited criteria. Patients were all community dwelling and had a responsible caregiver who lived with them and who was available to inform us about the activities of the AD patients.

Methods
All subjects had a nutritional assessment, which included measurements of anthropometric (weight, height, body mass index, skinfold thickness, and circumferences) and biological (albumin, prealbumin, C-reactive protein, and orosomucoid) markers. A Mini Nutritional Assessment (MNA; 35), used to evaluate the nutritional state of the elderly, was also conducted on every patient. Dietary assessment was accomplished as follows: for a period of 3 d, caregivers kept a food diary of everything the patients drank or ate. Portion size was expressed in household units. The ingredients of mixed dishes were specified. A dietitian collected and inspected these nutritional surveys and the results were analyzed by using the Dupin food-composition table (36) augmented with certain regional foods (37). The data for the dietary investigations are only available for all the subjects for the first year of follow-up.

A neuropsychologic and functional evaluation was performed on each patient by using many standardized and validated tools, such as the MMSE. The neuropsychologic evaluation included the following: the Cornell scale for depression (38; possible score: 0–38, with 0 being the best score), an adaptation of the Cohen-Mansfield Agitation Inventory for behavioral problems, the Reisberg scale (39; possible score: 0–7, with 0 being the best score), and the Hierarchic Dementia Scale (HDS; possible score: 0–200, with 0 being the best score) for dementia severity (40). Patient autonomy was screened by using the activities of daily living (ADL; possible score: 0–6, with 6 being the best score) and instrumental ADL (IADL; possible score: 0–8, with 8 being the best score) scales (41, 42). The Zarit scales were used to assess caregiver burden (Burden Interview; possible score: 0–88, with 0 being the best) and caregiver reactions to the AD patients' behavioral and autonomic disorders (Memory and Behavior Problems Checklist; possible score: 0–240, with 0 being the best) (43).

To study weight change, we considered a weight loss of 4% of body weight in 1 y to be significant (44). We researched significant weight loss during the first year of follow-up to identify subjects with weight variations and those whose weight remained stable throughout the study. We used the following equation:

The variable (the percentage of weight variation per year) was defined previously by White et al (15) to describe progressive weight variations during the study period. This variable does not account for weight fluctuations.

Statistics
A repeated-measures analysis of variance was used to detect statistically significant differences in mean anthropometric and neuropsychologic variables (weight, MMSE score, Cohen-Mansfield scale, Cornell scale, Reisberg scale, the Burden Interview, and the Memory and Behavior Problems Checklist). Correlational analyses between continuous independent variables and weight change were used to determine the predictive factors of weight change. Student's t test was used to compare means at baseline and those at 30 mo. Values are presented as means ± SDs.

Results
Results at 1 y
Seventy-six AD patients (MMSE score: 14.9 ± 6 at baseline; ADL score: 5.3 ± 1 at baseline) were followed for 1 y; 94% of these patients were living at home with a responsible caregiver. Thirty-four AD patients (44.7%) lost >4% of their initial body weight in 1 y, despite living at home (45). Surprisingly, a small number of our patients gained weight during the study period. Only the Burden Interview predicted the weight change in the total study pool (P = 0.03). Furthermore, weight loss was accompanied by a higher deterioration of those aspects of dementia explored by the MMSE and HDS. It was also accompanied by a diminution of anthropometric markers, but not of albumin, energy intake, or C-reactive protein. At this time point, only the Burden Interview was used in the statistical analysis of the caregiver's data.

Results at 30 mo
Fifty AD patients were followed for 30 mo. Cohort characteristics at baseline are summarized in Table 1. The longitudinal weight trends of the men and women were significantly different by two-factor repeated-measures analysis of variance (P = 0.05). These longitudinal weight trends occurred concurrently with a significant increase of dementia, as indicated by the MMSE and Reisberg scores (P = 0.0001), and with a significant increase in behavioral disorders (Cohen-Mansfield scale; P = 0.002) and caregiver burden (Burden Interview and the Memory and Behavior Problems Checklist; P = 0.01).

Discussion
Nutritional problems, especially unexplained weight loss, are frequent clinical findings in patients with AD (2, 7, 9). Weight loss is always a great concern for the clinical practitioner because it is an indicator of protein-energy malnutrition in the elderly and a predictive factor of mortality. White et al (14–16) studied several aspects of weight change in AD. They showed that weight loss is a predictive factor of mortality in elderly AD patients.

Our findings support an association between weight loss and AD. In the present study, >40% of AD patients showed significant weight loss, despite living at home, as described previously (14–16, 45). This weight loss occurred in the first stage of the disease, but also throughout the disease process. It is important to note that some patients with AD gained weight during the study period, as found by White et al (15). According to these authors, the finding of weight gain in some subjects suggests that body weight regulation is dysfunctional in AD. This dysfunction may be the consequence of the pathophysiology of AD because the complex regulation of energy intake involves sensory input, hormones, neurotransmitters, opioids, and the hypothalamus, which are disturbed during AD. For example, Grundman et al (19) showed that AD patients had significant brain atrophy in all measured brain regions, except the white matter, compared with normal control subjects. Decreased concentrations of NPY (in the temporal lobe, locus ceruleus, and tonsilla cerebelli), norepinephrine, and dopamine also were noted in AD patients (31).

In our study, the severity of dementia (Reisberg scale) was a predictive factor of weight loss and weight gain in AD (Tables 2 and 3), suggesting that the risk of weight change tends to increase with the severity and progression of AD. Moreover, weight loss was significantly associated with higher scores on standardized measures of caregivers' burden and stress (Table 2). The Memory and Behavior Problems Checklist seemed to be a good predictor of weight loss. It is possible that caregivers who consider themselves overburdened by the behavioral and autonomic disorders associated with the disease process are not willing to invest adequate resources to allow AD patients to properly nourish themselves. Many studies have shown negative effects of caregiving on caregivers (46). Caregivers may have an important and dramatic influence on the course of AD, particularly on the frequency and severity of behavioral problems and agitation and on whether the patient becomes institutionalized (47, 48). In addition, our results suggest that AD patients living with a highly distressed caregiver may experience greater weight loss. Moreover, Fredman and Daly (49) evaluated weight change and caregiver stress in caregivers of elderly patients discharged from a rehabilitation hospital. Weight change was significantly associated with higher scores on standardized measures of burden and stress. For these reasons, the assessment, management, and treatment of caregiver stress must be integral aspects of the total care of patients with dementia. It is possible that caregiver intervention (eg, individual treatment, support groups, education, and family therapy) will improve the AD patient's quality of life.

Given the serious consequences of weight loss (eg, muscle atrophy and accelerated loss of functional independence) and the influence of caregivers' stress on weight loss in AD patients, we developed a program of nutritional education and health promotion supported by the European Commission to detect weight changes and coordinate a nutritional intervention as soon as possible (50). This nutritional education program is intended to last 1 y for patients living at home with a caregiver. The aim of this program is to educate caregivers so that they can prevent weight loss and react positively when AD patients develop eating-behavior disorders. The program has been set up for 150 families in Toulouse (France), Brescia (Italy), and Barcelona (Spain). In this nutritional program, several tools are used to follow the nutritional status and body weight of AD patients, such as the MNA or the nutritional calendar. Through these various and complementary actions, the nutritional education program could prevent weight loss, improve the nutritional status of AD patients, and finally improve the quality of life of AD patients and their caregivers.

In conclusion, weight loss is commonly associated with AD. In our study, only the Burden Interview and the Memory and Behavior Problems Checklist predicted weight loss in AD. At present, intervention, such as a nutritional education program for caregivers, seems to be the best way to prevent weight loss and improve the nutritional status of AD patients.

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